Regeneration of the Developing Chick Elbow Joint Project Summary Synovial joints such as those that comprise the elbow, knee, and hip are extremely important for functioning in everyday life. Congenital defects, disease and trauma to synovial joints, in particular to the articular cartilage that comprises a joint, are debilitating o billions of people. Short of total joint replacement, therapies to bring the joint back to its norml functioning condition are sorely lacking. Impeding the progress of clinical measures is the inherent inability of articular cartilage to repair or regenerate itself. Thus, before joint repair procedures based on regeneration, i.e. regenerative medicine, are to be tested and utilized, there must be an understanding of the regeneration process of the tissues that comprise a joint. Until now, however, there has not been a study focused on regeneration of a synovial joint. The P.I. has developed and characterized a model of joint regeneration. Using the embryonic chick model, the P.I. has found that the presumptive elbow joint is able to regenerate following removal, and this ability is subsequently lost with increasing developmental age. Histological and molecular analyses have shown that regeneration of the joint follows a developmental program (redevelopment). We have also found that fibroblast growth factor (FGF) is able to induce regeneration in a non-regenerative model. Using histology, cell labeling, microscopy, proliferation assays, RT- PCR and in situ hybridization, the P.I. will analyze the initial stages o regeneration, cell migration and proliferation, in the context of gene expression patterns. Knowing the genetic and behavioral profile of the cells responsible for regeneration should enable us to begin to understand the requirements for regeneration to be initiated. The late stage of regeneration, morphogenesis, will be carefully analyzed using microCT scanning and histology. The induction of regeneration using FGF will be characterized with the goal of identifying critical upstream and downstream factors necessary for regeneration and the specific roles they play in the process. The long-term goal of this project is to elucidate the factors required to regenerate the tissues that make up a joint, including muscle, bone, and cartilage. The specific aims are designed to characterize the initial and later stages of regeneration as well as the FGF-induced regeneration response. This work will lay a foundation that will have significant implications in the fields of limb regeneration and regenerative medicine. PUBLIC HEALTH RELEVANCE: At some point in most everyone's life, joint integrity will be diminished either through trauma, disease, aging, or congenital defects. The research outlined in this proposal uses the first model of joint regeneration to begin to uncover the cues that are necessary for the tissues of the limb to initiate regeneration of a joint. By studying this process investigators will be that much closer to achieving regenerative repair in humans.